A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor γ with Excellent Effect on Insulin Resistance and Type 2 Diabetes

被引:15
作者
Liu, Hui-juan [1 ]
Zhang, Cheng-yu [1 ]
Song, Fei [1 ]
Xiao, Ting [1 ]
Meng, Jing [1 ]
Zhang, Qiang [1 ]
Liang, Cai-li [1 ]
Li, Shan [1 ]
Wang, Jing [1 ]
Zhang, Bo [1 ]
Liu, Yan-rong [1 ]
Sun, Tao [2 ]
Zhou, Hong-gang [2 ]
机构
[1] Tianjin Int Joint Acad Biomed, Tianjin Key Lab Mol Drug Res, Tianjin, Peoples R China
[2] Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China
关键词
PPAR-GAMMA; PROTEIN-METABOLISM; GLUCOSE-TRANSPORT; 3T3-L1; ADIPOCYTES; STREPTOZOTOCIN; RATS; LIVER; TRANSDUCTION; EXTRACT; OBESITY;
D O I
10.1124/jpet.115.223107
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Partial agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) reportedly reverse insulin resistance in patients with type 2 diabetes mellitus. In this work, a novel non-thiazolidinedione-partial PPAR gamma ligand, MDCCCL1636 [N-(4-hydroxyphenethyl)-3-mercapto-2-methylpropanamide], was investigated. The compound displayed partial agonist activity in biochemical and cell-based transactivation assays and reversed insulin resistance. MDCCCL1636 showed a potential antidiabetic effect on an insulin-resistance model of human hepatocarcinoma cells (HepG2). High-fat diet-fed streptozotocin-induced diabetic rats treated with MDCCCL1636 for 56 days displayed reduced fasting serum glucose and reversed dyslipidemia and pancreatic damage without significant weight gain. Furthermore, MDCCCL1636 had lower toxicity in vivo and in vitro than pioglitazone. MDCCCL1636 also potentiated glucose consumption and inhibited the impairment in insulin signaling targets, such as AKT, glycogen synthase kinase 3 beta, and glycogen synthase, in HepG2 human hepatoma cells. Overall, our results suggest that MDCCCL1636 is a promising candidate for the prevention and treatment of type 2 diabetes mellitus.
引用
收藏
页码:573 / 581
页数:9
相关论文
共 50 条
[41]   Peroxisome proliferator-activated receptors as molecular targets in relation to obesity and Type 2 diabetes [J].
Seda, Ondrej ;
Sedova, Lucie .
PHARMACOGENOMICS, 2007, 8 (06) :587-596
[42]   Telmisartan Improves Insulin Resistance of Skeletal Muscle Through Peroxisome Proliferator-Activated Receptor-δ Activation [J].
Li, Li ;
Luo, Zhidan ;
Yu, Hao ;
Feng, Xiaoli ;
Wang, Peijian ;
Chen, Jian ;
Pu, Yunfei ;
Zhao, Yu ;
He, Hongbo ;
Zhong, Jian ;
Liu, Daoyan ;
Zhu, Zhiming .
DIABETES, 2013, 62 (03) :762-774
[43]   Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-γ activation [J].
Hansmann, Georg ;
Wagner, Roger A. ;
Schellong, Stefan ;
Perez, Vinicio A. de Jesus ;
Urashima, Takashi ;
Wang, Lingli ;
Sheikh, Ahmad Y. ;
Suen, Renee S. ;
Stewart, Duncan J. ;
Rabinovitch, Marlene .
CIRCULATION, 2007, 115 (10) :1275-1284
[44]   Two Thiophenes Compounds Are Partial Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists [J].
Zheng, Zhihui ;
Yang, Yi ;
Shao, Huayi ;
Liu, Zongying ;
Lu, Xinhua ;
Xu, Yanni ;
He, Xiaobo ;
Jiang, Wei ;
Jiang, Qin ;
Zhao, Baohua ;
Zhang, Hua ;
Li, Zhuorong ;
Si, Shuyi .
BIOLOGICAL & PHARMACEUTICAL BULLETIN, 2011, 34 (10) :1631-1634
[45]   The discovery of novel isoflavone pan peroxisome proliferator-activated receptor agonists [J].
Matin, Azadeh ;
Doddareddy, Munikumar Reddy ;
Gavande, Navnath ;
Nammi, Srinivas ;
Groundwater, Paul W. ;
Roubin, Rebecca H. ;
Hibbs, David E. .
BIOORGANIC & MEDICINAL CHEMISTRY, 2013, 21 (03) :766-778
[46]   Involvement of Inducible 6-Phosphofructo-2-kinase in the Anti-diabetic Effect of Peroxisome Proliferator-activated Receptor γ Activation in Mice [J].
Guo, Xin ;
Xu, Kefeng ;
Zhang, Jifeng ;
Li, Honggui ;
Zhang, Weiyu ;
Wang, Huan ;
Lange, Alex J. ;
Chen, Y. Eugene ;
Huo, Yuqing ;
Wu, Chaodong .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (31) :23711-23720
[47]   Effects of Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Agonist, on the Urine and Urothelium of the Rat [J].
Suzuki, Shugo ;
Arnold, Lora L. ;
Pennington, Karen L. ;
Kakiuchi-Kiyota, Satoko ;
Wei, Min ;
Wanibuchi, Hideki ;
Cohen, Samuel M. .
TOXICOLOGICAL SCIENCES, 2010, 113 (02) :349-357
[48]   Regulation of adiponectin receptors in hepatocytes by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone [J].
Sun, X ;
Han, R ;
Wang, Z ;
Chen, Y .
DIABETOLOGIA, 2006, 49 (06) :1303-1310
[49]   The Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone Ameliorates Murine Lupus by Induction of Adiponectin [J].
Aprahamian, Tamar ;
Bonegio, Ramon G. ;
Richez, Christophe ;
Yasuda, Kei ;
Chiang, Lo-Ku ;
Sato, Kaori ;
Walsh, Kenneth ;
Rifkin, Ian R. .
JOURNAL OF IMMUNOLOGY, 2009, 182 (01) :340-346
[50]   Peroxisome proliferator-activated receptor-γ agonist pioglitazone suppresses experimental autoimmune uveitis [J].
Okunuki, Yoko ;
Usui, Yoshihiko ;
Nakagawa, Hayate ;
Tajima, Kazuki ;
Matsuda, Ryusaku ;
Ueda, Shunichiro ;
Hattori, Takaaki ;
Kezuka, Takeshi ;
Goto, Hiroshi .
EXPERIMENTAL EYE RESEARCH, 2013, 116 :291-297